B6i Characterization of Conduction in the Ventricles of Normal and Heterozygous Cx43 Knockout Mice Using Optical Mapping GREGORY E. MORLEY, PH.D., DHANANJAY VAIDYA, MBBS, FARAMARZ H. SAMIE. B.S., CECILIA LO, PH.D.,* MARIO DELMAR, M.D., PH.D., and JOSE JALIFE, M.D. From the' Department of Pharmacology, SUNY Health Science Center at Syracuse) Syracuse,' New York; and the *Department of Biology, University of Pennsylvania. Philadelphia. Pennsylvania Conduction in Normal and Cx43"'"'~ Mice. Introduction: Gap junction channels are important determinants of conduction in the heart and may play a central role in the development of lethal cardiac arrhythmias. The recent development of a Cx43-defic!ent moase has raised fundamental questions ahout the role of specific connexin i.soforms in intercellular communication in the heart. Although a homozygous null mutation of the Cx43 gene (Cx43~'~) is lethal, the heterozygous (Cx43^'^) animals survive to adulthood. Reports on the cardiac electrophysiologic phenotype of the Cx43^''~ mice are contradictory. Thus, the effects of a null mutation of a single Cx43 allele require reevaluation. Methods and Results: High-resolution video mapping techniques were used to study propa- gation in hearts from Cx43^'~ and littermate control (Cx43^'^) mice. Local conduction veloc- ities (CVs) and conduction patterns were quantitatively measured by determining conduction vectors. We undertook the characterization of ECG parameters and epicardial CVs of normal and Cx43^'^ mouse hearts. ECG measurements obtained from 12 Cx43^'^ and 6 Cx43^'~ age matched mice did not show diff'erenees in any parameter, including QRS duration (14.5 ± 0.9 and 15.7 ± 2.3 msec for Cx43"^'"^ and Cx43"^''~, respectively). In addition, using a sensitive method of detecting changes in local CV, video images of epicardial wave propagation revealed similar activation patterns and velocities in both groups of mice. Conclusion: A seasitive method that accurately measures local CVs throughout the ventricles revealed no changes in Cx43'^'~ mice, which is consi.stent with the demonstration that ECG parameter values in the heterozygous mice are the same as those in wild-type mice. (J Cardiovasc Electrophysiol. Vol. 10. pp. 1361-1375, October 1999) conduction velocity, reentry, arrhythmia, knockout mice, connexin-deficient mice Introduction The gap junction protein connexin43 (Cx43) is thought to play an essential role in the propa- This work was supporled by Program Project Grant POl HL 3^707 from the National Heart, Lung, and Blood Institute. Dr. Morley was a fellow ol* the North American Society of Pacing and Eiectrophys- iology, and F.H. Samie was a medical student fellow of the Howard Hughes Medical Institute. Address for correspondence: Gregory E. Morley. Ph.D.. Depart- ment (>r Phamiacology. SUNY Health Science Center. 766 Irving Avenue. Syracu.se, NY| 1321^ Fax: 315^64-8014; E-mail: hiorleyg@vax.cs.hscsyr.edu J Manuscript received 15 March 1999: Accepted for publication 8 June 1999. gation of the cardiac electrical impulse. The re- cent development of a Cx43-deficient mouse' has raised fundamental questions about the role of specific connexin isoforms in intercellular communication in the heart. Although a homozy- gous null mutation of the Cx43 gene (Cx43~'~) is lethal to the neouate, the heterozygous (Cx43"'"^~) animals survive to adulthood with no apparent abnormality. However, details on the cardiac electrophysiologic phenotype of the Cx43"^''~ mice are somewhat contradictory. Whereas no differences in macroscopic junc- tional conductance between cardiac myocytes have been detected,- a drop of up to 44% in